Reduced bone density, which often evolves into osteoporosis in aging populations, especially pre- and post-menopausal women, is an important health concern. Osteoporosis is defined clinically through the measurement of bone mineral density (BMD), which remains the best predictor of primary osteoporotic fractures (Kanis et al., Osteoporos. Int. 16:581, 2005). Systemic inflammation is frequently associated with accelerated bone reabsorption, which leads to bone loss. Various mechanisms, such as elevated PGE2, TNF-α, IL-1β and other pro-inflammatory cytokines, have been proposed to be involved with bone loss under inflammatory conditions (Hardy and Cooper, J. Endocrinol. 201:309, 2009).
It has been shown that NSAIDs inhibit the COX enzyme and decrease production of prostaglandins, which are involved in the regulation of bone turnover (Raisz et al., Osteoporos. Int. 3(Suppl 1):136, 1993). The use of cyclooxygenase-2 (COX-2) inhibitors has been demonstrated not only to impair load-induced bone formation, but also to prevent menopause-associated BMD loss (Richards et al., Osteoporos. Int. 17:1410, 2006). For example, diclofenac is an NSAID that inhibits both COX-1 and COX-2 enzymes (Richards et al., 2006). In a human clinical trial, diclofenac was almost as effective as conjugated estrogens for protection of bone loss in postmenopausal women (Bruce et al., Am. J. Med. 96:349, 1994). Cottrell et al. (Bone Joint Res. 2:41, 2013), have reported that a 5-lipoxygenase (LOX) inhibitor can enhance bone regeneration in an animal model. In human clinical trials in postmenopausal women, regular use of the combination of a COX-2 selective NSAID and aspirin has been shown to result in higher BMD at all skeletal sites, including whole body and total hip, as measured by bone density scanning (DXA) and both trabecular and cortical BMD of the lumbar spine by quantitative computer tomography (QCT) (Carbone et al., J. Bone Miner. Res. 18:1795, 2003).